Nu-2-benzothiazolylsulfonylbenzamide



Uflitd States F 3,139,436 N-Z-BENZOTHIAZOLYLSULFONYL- BENZAMIDE John B. Bicking, Lansdale, P2,, assignor to Merci: & Co., Inc., Railway, N..l., a corporation of New Jersey No Drawing. Original application June 9, 1958, Ser. No. 740,579. Divided and this application June 13, 1960, Ser. No. 35,428

- 1 Claim. (Cl. 260-4065) This invention relates torN-acylsulfonamides and to the preparation thereof. Such compounds have the generic formula 1 in which R and R are organo groups, and in which Q is selected from the group consisting of hydrogen and saltforming metals such as sodium and potassium. Numerous compounds of this class have been employed as dyestuffs, bacteriostatic agents, moth-proofing agents, catalysts, in-

hibitors in polymerizable mixtures, disinfectants, and for a variety of other purposes.

In the development of the presentinvention, the surprising discovery was made that certain of these N-acylsulfonamides are effective in regulating the sugar content of the blood of mammals, and in regulating the Respiratory Quotient (R.Q.). Symptoms such as excessively high sugar content of the. blood. and low Respiratory Quotient can be considered as diagnostic of deficiency in the utilization of carbohydrates by, the body, and can be modified by treatment with what are designated as hypoglycemic agents. However, the superiority of insulin among thehypoglycemic agents has been so outstanding that until recently only a few specialists'have been aware .that other hypoglycemic agents have been investigated. There has long been some dissatisfaction with insulin because of the need to administer it by injection. There has been a long standing demand for a synthetic chemical compound which could be employed for lowering the blood sugar level and/ or increasing the Respiratory Quotient of animals, and this demand has existed apart from the demand for an insulin substitute which could be fully equivalent to insulin.

Obese and elderly dogs sometimes develop diabetes mellitus, and previously it has been standard practice totreat such diabetes mellitus in dogs by a combination of diet blood sugar level in animals, whereby veterinarians treating animals with diabetes stead of injections. I

The investigation of the effectiveness of, N-acylsulfonamides having the above structural A formula as hypoglycemic agents disclosedfKa.) that certain N-acylsulfonamides possessed activity as hypoglycemic agents; and (b) that the correlation between the chemical structure. of the R and R groups and the eifectivness of the compounds as hypoglycemic agents did not appear to fall into any recognizable pattern, but instead, was quite specific to each control and daily injections .of. insulin. There has been :a long standing demand for a drug which would be suitable for oral administrationand capable of loweringthe mellitus could employ pills .in-

specific compound. Those compounds which possess sufficient hypoglycemic activity to be ofinterest aredis- 3,139,436 {Patented June 30, 1964 Ice possess significant hypoglycemic activity may be appreciated, but presently, because of the remarkable specificity and unpredictability as regards such compounds for such purpose, it is more convenient to place the major emphasis upon the specificity of the useful compounds and upon the membership of such useful compounds in the hypoglycemic agent class. i g j In accordance with the present invention, the blood sugar level of a mammal is lowered and/ or the Respiratory Quotient of a mammal is increased by treating the mammal with a small dosage of N-Z-benzothiazolylsulfonyl-benzamide. I

.The subject matter of the present invention can be fun .ther clarified by reference to several groups of data which are for convenience designated as examples without regard to whether they illustrate embodiments of the present invention. V p Y EXAMPLE 1 Cyclohexanesulfonamide is prepared from cyclohexylbromide by: bringing about a reaction between cyclohexylbromide and thiourea to form the hydrobromide salt of S-cyclohexylisothiourea; converting said salt to cyclohexanethiol by treatment with a basic aqueous solution; oxidizing and chlorinating the cyclohexanethiol by reaction with chlorine in acetic acid to form cyclohexylsulfonyl chloride; and treating the cyclohexyls'ulfonyl chloride in liquid ammonia to form cyclohexanesulfonamide.

' To 500ml. of ethanol, 326 g. (2 moles) of bromocyclohexane and g. (1.9 moles) of thiourea are added and refluxed for about 48 hours. The ethanol is removed from the reaction mixture under reduced pressure, and then 3-00 ml. of hot water is added, and the solvent again removed under reduced pressure, thereby precipitating a solid hydrobromide smt of S-cyclohexylisothiourea.

This solid is dissolved in 500 ml. of hot water, to which small amounts of 40% sodium hydroxide solution are added, care being taken not to add enough base to dissolve the cyclohexanethiol which forms as an oily layer. The

'cyclohexanethiol is dissolved in 1000 ml. of 70% acetic acid. The solution is cooled to below 10 C. and treated with chlorine as rapidly as possible without exceeding 10 C., using about 3.3 moles (a slight excess) of chlorine per mole of cyclohexanethiol. After dilution of the reaction mixture with 1000 ml. of ice water, the cyclohexylsulfonyl chloride formed is extracted three times with 400 ml. of ether. The combined extracts are washed with an aqueous solution of sodium hydrosulfite to remove any traces of .unreacted chlorine, and then with cold water. The solution is dried over sodium'sulfate. The ether is removed, leaving cyclohexylsulfonyl chloride. This compound is added carefully to 400ml. of liquid ammonia, and the excess ammonia is evaporated. The solid is dissolved in 1000 ml. of hot benzene and diluted with 700 ml. of hex- Jane, and the solution is cooled to permit the precipitation (of 77.4 g. (0.48 mole) of cyclohexanesulfonamide, repre sentinga 25% yield based uponthe thiourea employed.

The reaction between an organic compound containing a sulfonamide group as theonly reactive group and anorganic compound containing an acyl chloride as the only reactive group when conducted in the presence of an excess of weak tertiary amine capable of combining :with the hydrogen chloride, constitutes a reliable method for preparing the corresponding N-acyl sulfonamides. The purity of the N-acylsulfonamides is controlled predominantly by assuring the purity of the sulfonamide and acyl chloride participating in the final reaction. High purity is established by the sharpness of the melting point of the N-acyl sulfonamide. The proof of the structure of the N-acyl sulfonamide is established by the proof of the structure of the reactants plus an analysis of some of the elements in the end product of the reaction. The generic equation for this reliable reaction can be expressed as follows:

RSO NH +R'COC1+Tertiary Amine RSO NHCOR'+Tertiary Amine Hydrochloride EXAMPLE 2 N-cyclohexylsulfonyl-p-anisamide is prepared by the reaction of cyclohexanesulfonamide and anisoylchloride in H pyridine.

A solution is prepared by dissolving 11.4 g. (0.07 mole) of cyclohexanesulfonamide in 30 ml. of pyridine. An acid chloride is prepared by heating for 30 minutes on a steam bath a mixture of 11.4 g. (0.075 mole) of p-anisic acid and 9.5 g. (0.08 mole) of thionyl chloride, which acid chloride then is mixed with the pyridine solution and heated for 1.5 hours on the steam bath, thus forming a solution of the N-anisoylcyclohexanesulfonamide. This solution is cooled, diluted with 200 ml. of water, and acidified with hydrochloric acid. The resulting precipitate may be further purified by forming a precipitate of the sodium salt in 70 ml. of 5% sodium hydroxide solution, dissolving such salt in 200 ml. of water, and acidifying to precipitate the N-anisoylcyclohexanesulfonamide. This may be further purified by several recrystallizations from acetic acid. By this procedure, 8.3 g. (0.028 mole) of N-cyclohexylsulfonyl-p-anisamide are prepared, representing a 37% yield based upon the cyclohexanesulfonamide employed. The N-cyclohexylsulfonyl-p-anisamide has a melting point of 158 C. The compound has the formula C H NO S and is calculated to contain: 4.71% N; "56.55% C; and 6.44% H. The analysis found is: 4.68% N; 56.77% C; and 6.45% H. Such data are Within experimental accuracy, and confirm the composition of the compound to be as calculated.

The compound is soluble and stable in dilute alkali, such as an aqueous solution of about pH 11.5, but the sodium salt of the compound will precipitate if the alkali concentration is raised above about 1% sodium hydroxide. The compound may be conveniently utilized either in tablet form or as an aqueous alkaline solution consisting predominantly of Sorensons buffer (pH 7.8).

In establishing that the compound of this invention possesses hypoglycemic properties, reliable data are obtained by testing healthy animals to determine the extent of lowering of the blood sugar level and/ or the extent of increasing the Respiratory Quotient, and it is not necessary to restrict the testing to animals having an illness causing an abnormally high blood sugar level and/ or abnormally low Respiratory Quotient.

An established procedure for testing compounds for an abnormally high blood sugar level is as follows: A grou of eight young adult Holtzman rats weighing about 150 g. are fasted about 18 hours and the compound is administered in the designated dosages as an aqueous solution of its alkali metal salt. Concentrations are adjusted to give about 2 ml. per 100 g. of body weight. A blood sample is withdrawn from the tip of the tail before and two hours after administration of the compound, and the percentage of reduction of the blood sugar level two hours after oral administration of the compound is noted. The blood sugar is determined by the standard colorimetric method using an arsenomolybdate color reagent, as described by N. Nelson, J. Biol. Chem. 153, 375 (1944).

For each rat, the blood sugar level is measured as mg./ 100 ml. of whole blood and the value prior to treatment is treated as and subsequent measurements are expressed as a percent reduction of such initial values. Each dosage is evaluated by averaging the percent reduction in eight rats.

In establishing that N-2-benzothiazolylsulfonyl-benzamide is effective in increasing the Respiratory Quotient of animals, fasting young adult male rats are placed in a chamber, and air from the chamber is analyzed in the sonic gas analyzer. The Respiratory Quotient is measured before and 40 minutes after the oral administration of the stated doses of the compound to the rats. Table I shows the resulting data.

Table I EFFECT OF N-Z-BENZOTHIAZOLYL- SULFONYL-BENZAMIDE RESPIRA- TORY QUOTIEN'I Respiratory Dose, Quotient mg./kg. Increase Before After At oral dosages as high as 250 mg./kg. in rats, the acute toxicity, if any, is not noticeable.

EXAMPLE 3 A batch of tablets are prepared so that each tablet contains:

Mg. N 2-benzothiazolylsulfonyl-benzamide 50 Lactose 25 Dicalcium phosphate '25 Cornstarch 7 Acacia gum 2 Dispersion of 12% starch in water 2 Talc 2 Magnesium stearate 0.5

Total 113.5

References Cited in the file of this patent UNITED STATES PATENTS 2,595,334 Clapp et a1 May 6, 1952 2,891,960 Ruschig et a1 June 23, 1959 3,019,245 Novello Jan. 30, 1962 FOREIGN PATENTS 620,778 Great Britain Mar. 30, 1949 692,651 Great Britain June 10, 1953 

